DESCRIPTION: (Adapted from the application) Basal forebrain cholinergic neurons are prominently affected early in the course of Alzheimer's disease (AD). In rodent models, infusion of amyloid B peptide (AB, a candidate neurotoxin) into the basal forebrain affects cholinergic neurons, while sparing other neuronal populations. The mechanisms underlying this selective vulnerability of cholinergic neurons are presently unknown. To develop a model of selective cholinergic neuronal vulnerability, the applicants assayed the in vitro cytotoxicity of AB on a hybrid cholinergic septal cell line (SN56). SN56 cells, when differentiated with cAMP, express choline acetyltransferase (ChAT), and are killed by AB, whereas a related septal cell line (SN48), which does not express ChAT, is resistant to AB toxicity. In striking contrast to SN48 cells, the vulnerable SN56 cells express a tetraethylammonium (TEA)-sensitive delayed rectifier K+ current (IK), which is up-regulated by exposure to AB prior to cell death. Moreover,-TEA concentrations that block IK also protect SN56 cells from AB induced death, suggesting that alteration in this potassium current may underlie the vulnerability of these cholinergic cells to AB. This is relatively specific, as neither modulation of IK nor TEA protection was observed in SN56 cells after injury from hypoglycemia. These observations suggest that modulation of potassium currents may be a critical determinant of the selective vulnerability of cholinergic neurons to AB toxicity. However, the specific channels involved, the mechanisms underlying AB-induced IK enhancement, and the mechanisms linking IK enhancement with toxicity remain to be determined. To address these questions, the applicants propose to characterize IK in vulnerable SN56 cells, identify the K+ channel subunits underlying this current, and test whether susceptibility to AB may be conferred by the expression of specific K+ channel subunits. Furthermore, they will investigate the link between AB-induced IK enhancement, altered intracellular calcium concentration ([Ca2+]i), and AB toxicity. The applicants hypothesize that expression of specific K+ channels mediate the selective vulnerability of basal forebrain cholinergic neurons to candidate neurotoxins such as AB. The proposed experiments will test this novel hypothesis relating selective neuronal vulnerability in a neurodegenerative disorder to the expression of membrane ionic currents. Data from the proposed work will be critical to the development of specific strategies to modify cell vulnerability in patients with AD, and will be of great interest to investigators in a number of related fields, such as mechanisms of cell death, ion channel function, and other neurodegenerative illnesses. The candidate is committed to a research career. His background in septo-hippocampal cholinergic systems seems appropriate to understanding these structures' neurodegeneration in AD. The candidate's short-term goal is to understand the mechanisms underlying basal forebrain cholinergic cell vulnerability in AD. His long-term goal is to develop a strong independent program in AD research. The proposed studies will be carried out at the facilities of Baylor College of Medicine under the sponsorship of Stanley H. Appel, M.D., an internationally renowned investigator with long-standing interest in Alzheimer's disease and other neurodegenerative disorders.